JPH02282391A - 神経毒性損傷に有用なホスホノヒドロイソキノリン化合物 - Google Patents

神経毒性損傷に有用なホスホノヒドロイソキノリン化合物

Info

Publication number: JPH02282391A
Authority: JP; Japan
Prior art keywords: formula; hydrogen; carboxy; alkyl; formulas
Prior art date: 1988-10-21
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Pending

Application number

JP1273613A

Other languages

English (en)

Japanese (ja)

Inventor

Alexis A Cordi

アレクシス　エイ．コーディ

Michael L Vazquez

マイクル　エル．バズクェツ

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

GD Searle LLC

Original Assignee

GD Searle LLC

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1988-10-21

Filing date

1989-10-20

Publication date

1990-11-19

1988-10-21 Priority claimed from US07/260,839 external-priority patent/US4997821A/en

1989-10-20 Application filed by GD Searle LLC filed Critical GD Searle LLC

1990-11-19 Publication of JPH02282391A publication Critical patent/JPH02282391A/ja

Status Pending legal-status Critical Current

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 154
231100000189 neurotoxic Toxicity 0.000 title abstract description 10
230000002887 neurotoxic effect Effects 0.000 title abstract description 10
230000003902 lesion Effects 0.000 title 1
125000000217 alkyl group Chemical group 0.000 claims abstract description 124
-1 sulfonamide compound Chemical class 0.000 claims abstract description 58
125000001188 haloalkyl group Chemical group 0.000 claims abstract description 32
238000000034 method Methods 0.000 claims abstract description 29
125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 27
125000003118 aryl group Chemical group 0.000 claims abstract description 26
239000002253 acid Substances 0.000 claims abstract description 25
239000011541 reaction mixture Substances 0.000 claims abstract description 23
229940124530 sulfonamide Drugs 0.000 claims abstract description 20
125000002252 acyl group Chemical group 0.000 claims abstract description 18
150000003456 sulfonamides Chemical class 0.000 claims abstract description 11
238000007363 ring formation reaction Methods 0.000 claims abstract description 8
239000000010 aprotic solvent Substances 0.000 claims abstract description 3
125000001475 halogen functional group Chemical group 0.000 claims abstract 41
NXUOGRIOEQVHRG-UHFFFAOYSA-N 5-phosphono-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;hydrochloride Chemical compound Cl.C1=CC=C(P(O)(O)=O)C2=C1CNC(C(=O)O)C2 NXUOGRIOEQVHRG-UHFFFAOYSA-N 0.000 claims abstract 4
125000003342 alkenyl group Chemical group 0.000 claims abstract 4
229910052739 hydrogen Inorganic materials 0.000 claims description 129
239000001257 hydrogen Substances 0.000 claims description 128
239000000126 substance Substances 0.000 claims description 96
150000002431 hydrogen Chemical class 0.000 claims description 77
239000000203 mixture Substances 0.000 claims description 48
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 45
125000003545 alkoxy group Chemical group 0.000 claims description 44
125000003710 aryl alkyl group Chemical group 0.000 claims description 28
229920006395 saturated elastomer Polymers 0.000 claims description 23
125000004043 oxo group Chemical group O=* 0.000 claims description 22
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
125000004437 phosphorous atom Chemical group 0.000 claims description 21
229910052698 phosphorus Inorganic materials 0.000 claims description 21
125000000753 cycloalkyl group Chemical group 0.000 claims description 18
239000002904 solvent Substances 0.000 claims description 15
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 14
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
150000003839 salts Chemical class 0.000 claims description 13
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
238000004519 manufacturing process Methods 0.000 claims description 9
125000005592 polycycloalkyl group Polymers 0.000 claims description 9
125000001424 substituent group Chemical group 0.000 claims description 9
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
VRDCPZSTZJNJOF-UHFFFAOYSA-N 5-phosphono-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1=CC=C(P(O)(O)=O)C2=C1CNC(C(=O)O)C2 VRDCPZSTZJNJOF-UHFFFAOYSA-N 0.000 claims description 7
229940098779 methanesulfonic acid Drugs 0.000 claims description 6
125000005037 alkyl phenyl group Chemical group 0.000 claims description 5
YBYCJQQRZPXLHU-UHFFFAOYSA-N 1,2,3,4,5,6,7,8-octahydroisoquinoline Chemical compound C1CNCC2=C1CCCC2 YBYCJQQRZPXLHU-UHFFFAOYSA-N 0.000 claims description 4
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
239000003085 diluting agent Substances 0.000 claims description 4
239000003937 drug carrier Substances 0.000 claims description 3
UJXAMQMJRZKIDZ-UHFFFAOYSA-N 5-phosphono-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid Chemical compound C1NC(C(=O)O)CC2C1CCCC2P(O)(O)=O UJXAMQMJRZKIDZ-UHFFFAOYSA-N 0.000 claims description 2
239000008194 pharmaceutical composition Substances 0.000 claims description 2
125000004663 dialkyl amino group Chemical group 0.000 claims 6
UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims 4
YUZYSZUYNNZCGN-UHFFFAOYSA-N 5-(phosphonomethyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1=CC=C2CNC(C(=O)O)CC2=C1CP(O)(O)=O YUZYSZUYNNZCGN-UHFFFAOYSA-N 0.000 claims 4
QASVNZQGTCVOJE-UHFFFAOYSA-N (3-ethoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)phosphonic acid Chemical compound C1=CC=C(P(O)(O)=O)C2=C1CNC(C(=O)OCC)C2 QASVNZQGTCVOJE-UHFFFAOYSA-N 0.000 claims 3
VRDCPZSTZJNJOF-MRVPVSSYSA-N C1=CC=C(P(O)(O)=O)C2=C1CN[C@@H](C(=O)O)C2 Chemical compound C1=CC=C(P(O)(O)=O)C2=C1CN[C@@H](C(=O)O)C2 VRDCPZSTZJNJOF-MRVPVSSYSA-N 0.000 claims 3
VRDCPZSTZJNJOF-QMMMGPOBSA-N (3S)-5-phosphono-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1=CC=C(P(O)(O)=O)C2=C1CN[C@H](C(=O)O)C2 VRDCPZSTZJNJOF-QMMMGPOBSA-N 0.000 claims 2
GIFHYRZMVBLTHY-UHFFFAOYSA-N 5-(2-phosphonoethenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1=CC=C(C=CP(O)(O)=O)C2=C1CNC(C(=O)O)C2 GIFHYRZMVBLTHY-UHFFFAOYSA-N 0.000 claims 2
KOFSFJYKXNRFNJ-UHFFFAOYSA-N 5-[ethoxy(hydroxy)phosphoryl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1NC(C(O)=O)CC2=C1C=CC=C2P(O)(=O)OCC KOFSFJYKXNRFNJ-UHFFFAOYSA-N 0.000 claims 2
YVNYDIUCAAKTAQ-UHFFFAOYSA-N 5-phosphono-1,2,3,4,5,6,7,8-octahydroisoquinoline-3-carboxylic acid Chemical compound C1NC(C(=O)O)CC2=C1CCCC2P(O)(O)=O YVNYDIUCAAKTAQ-UHFFFAOYSA-N 0.000 claims 2
HLQZJZJEGMDDLF-UHFFFAOYSA-N 5-phosphono-1,2,3,4,5,8-hexahydroisoquinoline-3-carboxylic acid Chemical compound C1C=CC(P(O)(O)=O)C2=C1CNC(C(=O)O)C2 HLQZJZJEGMDDLF-UHFFFAOYSA-N 0.000 claims 2
BVKFNWVWIAJPNC-UHFFFAOYSA-N 6-chloro-5-phosphono-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1=CC(Cl)=C(P(O)(O)=O)C2=C1CNC(C(=O)O)C2 BVKFNWVWIAJPNC-UHFFFAOYSA-N 0.000 claims 2
JEYMAZTZPMOASD-UHFFFAOYSA-N 6-methyl-5-phosphono-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1NC(C(O)=O)CC2=C(P(O)(O)=O)C(C)=CC=C21 JEYMAZTZPMOASD-UHFFFAOYSA-N 0.000 claims 2
ODEANIVOQYVSAJ-UHFFFAOYSA-N 7-chloro-5-phosphono-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1=C(Cl)C=C(P(O)(O)=O)C2=C1CNC(C(=O)O)C2 ODEANIVOQYVSAJ-UHFFFAOYSA-N 0.000 claims 2
NENLYAQPNATJSU-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline Chemical compound C1NCCC2CCCCC21 NENLYAQPNATJSU-UHFFFAOYSA-N 0.000 claims 1
CVFYWOCNYFUDCX-UHFFFAOYSA-N 1,2,3,4,5,8-hexahydroisoquinoline Chemical compound C1C=CCC2=C1CNCC2 CVFYWOCNYFUDCX-UHFFFAOYSA-N 0.000 claims 1
UWMGGKFMOJLPMT-UHFFFAOYSA-N 5-(2-phosphonoethyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1=CC=C2CNC(C(=O)O)CC2=C1CCP(O)(O)=O UWMGGKFMOJLPMT-UHFFFAOYSA-N 0.000 claims 1
JQOUGGPGOWRLPX-UHFFFAOYSA-N 6-methyl-1,2,3,4-tetrahydroisoquinoline Chemical compound C1NCCC2=CC(C)=CC=C21 JQOUGGPGOWRLPX-UHFFFAOYSA-N 0.000 claims 1
UUGKOGJJUBEIDM-UHFFFAOYSA-N 7-methyl-5-phosphono-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1NC(C(O)=O)CC2=C1C=C(C)C=C2P(O)(O)=O UUGKOGJJUBEIDM-UHFFFAOYSA-N 0.000 claims 1
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
230000006378 damage Effects 0.000 abstract description 9
230000008569 process Effects 0.000 abstract description 5
239000000463 material Substances 0.000 abstract description 4
230000002921 anti-spasmodic effect Effects 0.000 abstract description 2
239000000812 cholinergic antagonist Substances 0.000 abstract description 2
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
229910001868 water Inorganic materials 0.000 description 34
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
239000000047 product Substances 0.000 description 28
239000007787 solid Substances 0.000 description 28
238000006243 chemical reaction Methods 0.000 description 26
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 25
239000000243 solution Substances 0.000 description 25
WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 21
230000027455 binding Effects 0.000 description 19
229940049906 glutamate Drugs 0.000 description 19
239000003921 oil Substances 0.000 description 19
125000005843 halogen group Chemical group 0.000 description 18
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
239000012141 concentrate Substances 0.000 description 15
229930195712 glutamate Natural products 0.000 description 15
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
235000008504 concentrate Nutrition 0.000 description 14
239000000543 intermediate Substances 0.000 description 14
238000000159 protein binding assay Methods 0.000 description 14
QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
238000010992 reflux Methods 0.000 description 11
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
125000004432 carbon atom Chemical group C* 0.000 description 10
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
239000011734 sodium Substances 0.000 description 9
PIEPQKCYPFFYMG-UHFFFAOYSA-N tris acetate Chemical compound CC(O)=O.OCC(N)(CO)CO PIEPQKCYPFFYMG-UHFFFAOYSA-N 0.000 description 8
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 7
206010021143 Hypoxia Diseases 0.000 description 7
238000007792 addition Methods 0.000 description 7
239000003054 catalyst Substances 0.000 description 7
239000002552 dosage form Substances 0.000 description 7
125000004435 hydrogen atom Chemical group [H]* 0.000 description 7
238000011534 incubation Methods 0.000 description 7
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
239000000377 silicon dioxide Substances 0.000 description 7
238000003756 stirring Methods 0.000 description 7
230000000694 effects Effects 0.000 description 6
102000005962 receptors Human genes 0.000 description 6
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239000004471 Glycine Substances 0.000 description 5
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DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
VLSMHEGGTFMBBZ-OOZYFLPDSA-M Kainate Chemical compound CC(=C)[C@H]1C[NH2+][C@H](C([O-])=O)[C@H]1CC([O-])=O VLSMHEGGTFMBBZ-OOZYFLPDSA-M 0.000 description 5
HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 5
239000005557 antagonist Substances 0.000 description 5
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125000006239 protecting group Chemical group 0.000 description 5
229910052708 sodium Inorganic materials 0.000 description 5
230000000946 synaptic effect Effects 0.000 description 5
238000012360 testing method Methods 0.000 description 5
MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 description 4
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150000007513 acids Chemical class 0.000 description 4
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
125000001246 bromo group Chemical group Br* 0.000 description 4
210000003169 central nervous system Anatomy 0.000 description 4
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230000001419 dependent effect Effects 0.000 description 4
239000003814 drug Substances 0.000 description 4
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238000000926 separation method Methods 0.000 description 4
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WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 2
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229940125898 compound 5 Drugs 0.000 description 1
238000013270 controlled release Methods 0.000 description 1
238000007796 conventional method Methods 0.000 description 1
238000001816 cooling Methods 0.000 description 1
238000012937 correction Methods 0.000 description 1
239000013078 crystal Substances 0.000 description 1
125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
150000005690 diesters Chemical class 0.000 description 1
238000010790 dilution Methods 0.000 description 1
239000012895 dilution Substances 0.000 description 1
125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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238000003821 enantio-separation Methods 0.000 description 1
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CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
MWQBWSPPTQGZII-UHFFFAOYSA-N ethoxy(phenyl)phosphinic acid Chemical compound CCOP(O)(=O)C1=CC=CC=C1 MWQBWSPPTQGZII-UHFFFAOYSA-N 0.000 description 1
FPULFENIJDPZBX-UHFFFAOYSA-N ethyl 2-isocyanoacetate Chemical compound CCOC(=O)C[N+]#[C-] FPULFENIJDPZBX-UHFFFAOYSA-N 0.000 description 1
238000011156 evaluation Methods 0.000 description 1
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125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 1
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
238000001640 fractional crystallisation Methods 0.000 description 1
239000012634 fragment Substances 0.000 description 1
239000012458 free base Substances 0.000 description 1
239000001530 fumaric acid Substances 0.000 description 1
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239000003193 general anesthetic agent Substances 0.000 description 1
239000012362 glacial acetic acid Substances 0.000 description 1
239000000174 gluconic acid Substances 0.000 description 1
235000012208 gluconic acid Nutrition 0.000 description 1
229940097043 glucuronic acid Drugs 0.000 description 1
239000004220 glutamic acid Substances 0.000 description 1
235000013922 glutamic acid Nutrition 0.000 description 1
150000004795 grignard reagents Chemical class 0.000 description 1
229910052736 halogen Inorganic materials 0.000 description 1
150000002367 halogens Chemical class 0.000 description 1
238000003306 harvesting Methods 0.000 description 1
125000000623 heterocyclic group Chemical group 0.000 description 1
GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
238000004128 high performance liquid chromatography Methods 0.000 description 1
238000000265 homogenisation Methods 0.000 description 1
150000003840 hydrochlorides Chemical class 0.000 description 1
XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
229940071870 hydroiodic acid Drugs 0.000 description 1
125000002768 hydroxyalkyl group Chemical group 0.000 description 1
230000002218 hypoglycaemic effect Effects 0.000 description 1
230000001146 hypoxic effect Effects 0.000 description 1
239000007943 implant Substances 0.000 description 1
239000012535 impurity Substances 0.000 description 1
239000003999 initiator Substances 0.000 description 1
230000000977 initiatory effect Effects 0.000 description 1
238000002347 injection Methods 0.000 description 1
239000007924 injection Substances 0.000 description 1
229910052500 inorganic mineral Inorganic materials 0.000 description 1
239000002198 insoluble material Substances 0.000 description 1
238000007918 intramuscular administration Methods 0.000 description 1
239000007927 intramuscular injection Substances 0.000 description 1
238000010255 intramuscular injection Methods 0.000 description 1
238000010253 intravenous injection Methods 0.000 description 1
239000012948 isocyanate Substances 0.000 description 1
150000002513 isocyanates Chemical class 0.000 description 1
125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 1
238000005304 joining Methods 0.000 description 1
229960003299 ketamine Drugs 0.000 description 1
HCZHHEIFKROPDY-UHFFFAOYSA-N kynurenic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC(=O)C2=C1 HCZHHEIFKROPDY-UHFFFAOYSA-N 0.000 description 1
239000004310 lactic acid Substances 0.000 description 1
235000014655 lactic acid Nutrition 0.000 description 1
239000003446 ligand Substances 0.000 description 1
239000007937 lozenge Substances 0.000 description 1
239000000314 lubricant Substances 0.000 description 1
229910052943 magnesium sulfate Inorganic materials 0.000 description 1
235000019341 magnesium sulphate Nutrition 0.000 description 1
VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
239000011976 maleic acid Substances 0.000 description 1
229960002510 mandelic acid Drugs 0.000 description 1
239000003550 marker Substances 0.000 description 1
229960003194 meglumine Drugs 0.000 description 1
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
239000011707 mineral Substances 0.000 description 1
235000010755 mineral Nutrition 0.000 description 1
238000002156 mixing Methods 0.000 description 1
239000012452 mother liquor Substances 0.000 description 1
ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
125000001624 naphthyl group Chemical group 0.000 description 1
210000000653 nervous system Anatomy 0.000 description 1
230000001537 neural effect Effects 0.000 description 1
230000002981 neuropathic effect Effects 0.000 description 1
230000000324 neuroprotective effect Effects 0.000 description 1
231100000228 neurotoxicity Toxicity 0.000 description 1
230000007135 neurotoxicity Effects 0.000 description 1
239000002581 neurotoxin Substances 0.000 description 1
231100000618 neurotoxin Toxicity 0.000 description 1
229910052759 nickel Inorganic materials 0.000 description 1
229910017604 nitric acid Inorganic materials 0.000 description 1
239000012299 nitrogen atmosphere Substances 0.000 description 1
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
239000001301 oxygen Substances 0.000 description 1
229910052763 palladium Inorganic materials 0.000 description 1
WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
239000011713 pantothenic acid Substances 0.000 description 1
229940055726 pantothenic acid Drugs 0.000 description 1
235000019161 pantothenic acid Nutrition 0.000 description 1
101150093826 par1 gene Proteins 0.000 description 1
230000001575 pathological effect Effects 0.000 description 1
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125000005004 perfluoroethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
208000033300 perinatal asphyxia Diseases 0.000 description 1
239000000546 pharmaceutical excipient Substances 0.000 description 1
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
239000010452 phosphate Substances 0.000 description 1
PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical class NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 description 1
OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
239000011574 phosphorus Substances 0.000 description 1
230000035479 physiological effects, processes and functions Effects 0.000 description 1
239000006187 pill Substances 0.000 description 1
229910052697 platinum Inorganic materials 0.000 description 1
BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
230000001242 postsynaptic effect Effects 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
239000011591 potassium Substances 0.000 description 1
230000003389 potentiating effect Effects 0.000 description 1
238000002360 preparation method Methods 0.000 description 1
238000002953 preparative HPLC Methods 0.000 description 1
239000003755 preservative agent Substances 0.000 description 1
229940097325 prolactin Drugs 0.000 description 1
238000011321 prophylaxis Methods 0.000 description 1
235000019260 propionic acid Nutrition 0.000 description 1
239000003586 protic polar solvent Substances 0.000 description 1
238000010791 quenching Methods 0.000 description 1
230000000171 quenching effect Effects 0.000 description 1
IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
150000003254 radicals Chemical class 0.000 description 1
230000002285 radioactive effect Effects 0.000 description 1
239000002287 radioligand Substances 0.000 description 1
239000002994 raw material Substances 0.000 description 1
230000035484 reaction time Effects 0.000 description 1
238000001525 receptor binding assay Methods 0.000 description 1
238000000611 regression analysis Methods 0.000 description 1
MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
229960004889 salicylic acid Drugs 0.000 description 1
238000007086 side reaction Methods 0.000 description 1
239000000741 silica gel Substances 0.000 description 1
229910002027 silica gel Inorganic materials 0.000 description 1
RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
239000001632 sodium acetate Substances 0.000 description 1
235000017281 sodium acetate Nutrition 0.000 description 1
159000000000 sodium salts Chemical class 0.000 description 1
239000002689 soil Substances 0.000 description 1
241000894007 species Species 0.000 description 1
230000003595 spectral effect Effects 0.000 description 1
239000008117 stearic acid Substances 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
239000007929 subcutaneous injection Substances 0.000 description 1
238000010254 subcutaneous injection Methods 0.000 description 1
238000000859 sublimation Methods 0.000 description 1
230000008022 sublimation Effects 0.000 description 1
238000006467 substitution reaction Methods 0.000 description 1
229960002317 succinimide Drugs 0.000 description 1
239000005720 sucrose Substances 0.000 description 1
229950000244 sulfanilic acid Drugs 0.000 description 1
125000000565 sulfonamide group Chemical group 0.000 description 1
239000000829 suppository Substances 0.000 description 1
239000004094 surface-active agent Substances 0.000 description 1
210000002182 synaptic membrane Anatomy 0.000 description 1
230000005062 synaptic transmission Effects 0.000 description 1
238000001308 synthesis method Methods 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
125000005490 tosylate group Chemical group 0.000 description 1
231100000331 toxic Toxicity 0.000 description 1
230000002588 toxic effect Effects 0.000 description 1
238000000844 transformation Methods 0.000 description 1
UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
229910052721 tungsten Inorganic materials 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
230000002747 voluntary effect Effects 0.000 description 1
229910052727 yttrium Inorganic materials 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/62—Isoquinoline or hydrogenated isoquinoline ring systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4021—Esters of aromatic acids (P-C aromatic linkage)

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
General Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Public Health (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Pharmacology & Pharmacy (AREA)
Medicinal Chemistry (AREA)
Animal Behavior & Ethology (AREA)
Veterinary Medicine (AREA)
Biochemistry (AREA)
Molecular Biology (AREA)
Pain & Pain Management (AREA)
Hospice & Palliative Care (AREA)
Psychiatry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

JP1273613A 1988-10-21 1989-10-20 神経毒性損傷に有用なホスホノヒドロイソキノリン化合物 Pending JPH02282391A (ja)

Applications Claiming Priority (4)

Application Number	Priority Date	Filing Date	Title
US260839		1988-10-21
US07/260,839 US4997821A (en)	1988-10-21	1988-10-21	Phosphono-hydroisoquinoline compounds useful in reducing neurotoxic injury
US41809289A	1989-10-12	1989-10-12
US418092		1989-10-12

Publications (1)

Publication Number	Publication Date
JPH02282391A true JPH02282391A (ja)	1990-11-19

Family

ID=26948203

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
JP1273613A Pending JPH02282391A (ja)	1988-10-21	1989-10-20	神経毒性損傷に有用なホスホノヒドロイソキノリン化合物

Country Status (3)

Country	Link
EP (1)	EP0364996A3 (fr)
JP (1)	JPH02282391A (fr)
CA (1)	CA2000901A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US5506219A (en) *	1988-08-29	1996-04-09	E. R. Squibb & Sons, Inc.	Pyridine anchors for HMG-CoA reductase inhibitors
AU6368090A (en) *	1989-10-03	1991-04-11	Warner-Lambert Company	Substituted carboxytetrahydroisoquinolines and derivatives thereof having pharmaceutical activity
DE4104257A1 (de) *	1991-02-13	1992-08-20	Boehringer Ingelheim Kg	Verwendung von anellierten tetrahydropyridinessigsaeurederivaten fuer die behandlung neurologischer erkrankungen
EP3427729A1 (fr)	2017-07-13	2019-01-16	Paris Sciences et Lettres - Quartier Latin	Probénécide destiné à être utilisé dans le traitement de maladies, troubles ou états épileptiques

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
PH23848A (en) *	1985-05-24	1989-11-23	Ciba Geigy Ag	Certain phosphonic acids and derivatives
ATE60776T1 (de) *	1986-11-21	1991-02-15	Ciba Geigy Ag	Ungesaettigte phosphonsaeure und derivate.

1989
- 1989-10-17 CA CA002000901A patent/CA2000901A1/fr not_active Abandoned
- 1989-10-19 EP EP19890119378 patent/EP0364996A3/fr not_active Withdrawn
- 1989-10-20 JP JP1273613A patent/JPH02282391A/ja active Pending

Also Published As

Publication number	Publication date
EP0364996A2 (fr)	1990-04-25
EP0364996A3 (fr)	1991-04-03
CA2000901A1 (fr)	1990-04-21

Publication	Publication Date	Title
KR910001042B1 (ko)	1991-02-21	4-아미노알킬-2(3h)-인돌론 및 이의 제조방법
CA2146259C (fr)	1998-04-07	Derives de substitution de benzylaminoquinuclidines
EP1753762B1 (fr)	2014-03-19	Synthese d'esters cycliques induite par l'acide de lewis
AU2019234185A1 (en)	2020-10-01	Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
OA12016A (en)	2006-04-19	Tricyclic inhibitors of poly(adp-ribose)polymerases.
PL171921B1 (pl)	1997-06-30	Sposób wytwarzania nowych pochodnych podstawionej 3-aminochinuklidyny PL PL PL PL PL
JPH04234857A (ja)	1992-08-24	３，５−ジ置換２−イソキサゾリンおよびイソキサゾール、それらの製法およびそれらを含有する薬学的組成物
JP2930366B2 (ja)	1999-08-03	置換アミノアルキルホスフィン酸
EP0539057B1 (fr)	1997-07-16	Acides benzimidazole phosphono-aminés
WO2014047370A1 (fr)	2014-03-27	Composés fluoroalkyl benzodiazépinones
US5633237A (en)	1997-05-27	Imidazo[1,2-a]pyridinylalkyl phosphonic acid compounds for treatment of neurotoxic injury
JP2025156455A (ja)	2025-10-14	チアゾロ［５，４－ｂ］ピリジンＭＡＬＴ－１阻害剤
JP2778832B2 (ja)	1998-07-23	Ｇａｂａ−ｂアンタゴニストとしての２−置換モルホリンおよびチオモルホリン誘導体
JPH02282391A (ja)	1990-11-19	神経毒性損傷に有用なホスホノヒドロイソキノリン化合物
US5464843A (en)	1995-11-07	Imidazo[1,2-a]pyridinyldiacid compounds for cognitive enhancement and for treatment of cognitive disorders and neutrotoxic injury
US5668121A (en)	1997-09-16	Glutamate (NMDA) receptor antagonists
EP0266308B1 (fr)	1991-07-24	Dérivés de l'indolo-pyrazino-benzodiazépine
US4997821A (en)	1991-03-05	Phosphono-hydroisoquinoline compounds useful in reducing neurotoxic injury
AU686722B2 (en)	1998-02-12	Heterocyclic compounds
JPH03130296A (ja)	1991-06-04	４―置換２―アミノアルク―３―エン酸
US5177240A (en)	1993-01-05	O-phosphono(alkyl)-n-sulfonyl-phenyl-alanine derivatives useful as intermediates for preparation of phosphono-hydroisoquinolines
US6083943A (en)	2000-07-04	Substituted azaheterocyclecarboxylic acid
Ruiz-Gómez et al.	2007	Dearomatizing Anionic Cyclization of N-Alkyl-N-benzyl (dinaphthyl) phosphinamides. A Facile Route to γ-(Amino) dihydronaphthalenylphosphinic Acids
JPS5989684A (ja)	1984-05-23	〔１，２，４〕トリアゾロ〔４，３―ａ〕キノキサリン―４―アミン誘導体
JP2001278890A (ja)	2001-10-10	アリール又はヘテロアリールキノリニルホスホン酸化合物、これらの製造方法及びこれらを含む薬剤組成物